Infectious diseases caused by a number of different kinds of viruses such as influenza viruses and hepatitis viruses have been perceived as a problem, and various antiviral agents are under study. The virus propagation cycle is divided roughly into infection of viruses to cells, replication of the viruses in the infected cells, and release of propagated viruses to the outside of the infected cells. Approaches are being considered for each of these steps.
The virus propagation cycle will be explained briefly. First, a virus having an envelope identifies a sialic acid receptor on the surface of a cell and binds thereto. This triggers the endocytosis of the cell, and the virus is incorporated into the cell while being enclosed by a cell membrane. Then, when the inside of a phagosome enclosing the virus becomes acidic, by a membrane fusion activity of a membrane fusion protein (e.g., hemagglutinin (HA) or the like) present in the envelope, the membrane of the phagosome (derived from the cell) and the envelope of the virus (the membrane of the virus) fuse with each other. When this membrane fusion occurs, further by the action of a protein called M2, the membrane is perforated (uncoating), whereby RNA of the virus is released into the cell. The above-described process is a mechanism of infection of the virus to the cell. Next, a mechanism of replication and release of the virus in the infected cell will be described. The RNA of the virus released into the cell further is transported to a cell nucleus of the infected cell. Using this viral RNA, RNA, proteins, and the like that serve as components of new viruses are synthesized in a large quantity in the infected cell. Then, the virus genome and some of the proteins synthesized in the infected cell together form a virus core, which then moves to the cell membrane. Also, the synthesized membrane fusion protein and neuraminidase (NA) move to the cell membrane and bind thereto. Then, the virus that has moved to the cell membrane is packed with the cell membrane having the membrane fusion protein and NA, and then buds from the surface of the cell membrane. At this time, the budding virus binds to a sialic acid receptor present on the surface of the cell membrane of the infected cell. However, the budding virus is released to the outside of the cell when NA on the cell membrane cleaves the sialic acid receptor. The infection, replication, and release of the virus are performed in the above-described manner, and uninfected cells will be infected with the released viruses.
As antiviral agents, specifically, M2 inhibitors that approach the cell infection step (Non-Patent Document 1 and Non-Patent Document 2) and NA inhibitors that approach the replication and release step (Non-Patent Document 3 to Non-Patent Document 5) have been developed for influenza viruses, for example. The former are pharmaceutical compositions that inhibit the action of a protein M2 embedded in the envelope of a virus, and for example, hydrochloric acid amantadine is known. By these pharmaceutical compositions, the action of M2 is inhibited, whereby the uncoating of a virus in the infected cell is inhibited. Thus, there is no chance that RNA derived from the virus is transported to a cell nucleus, so that the synthesis of viral RNA and proteins itself can be blocked. On the other hand, the latter are pharmaceutical compositions that inhibit the action of NA present in the envelope of a virus, and for example, zanamivir (registered trademark “Relenza”), oseltamivir (oseltamivir phosphate; registered trademark “Tamiflu”), and the like are known. By these pharmaceutical compositions, the action of NA is inhibited, so that, even if the virus is replicated in the infected cell, NA cannot cleave the bonding between the budding virus and a sialic acid receptor. Thus, the budding virus cannot be separated from the membrane surface of the infected cell, and it eventually agglutinates.
However, the M2 inhibitors as the former are not effective against viruses lacking M2, such as influenza B viruses, and their side effects also are seen as a problem. Regarding the NA inhibitors as the latter, their high drug price and side effects are seen as problems. Furthermore, regarding either type of the antiviral agents, there is a concern about the development of viruses resistant thereto. In view of these circumstances, there is a demand for a pharmaceutical composition that targets a different step in the virus propagation cycle than conventional pharmaceutical compositions and also has excellent safety.